Substituted imidazo[1,2-a]pyrimidines as HIV viral DNA integrase inhibitors

ABSTRACT

The invention encompasses a series of bicyclic heterocyclic compounds of Formula I which are inhibitors of HIV integrase and prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser. No. 60/713,080, filed Aug. 31, 2005.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) has been identified as the etiological agent responsible for acquired immune deficiency syndrome (AIDS), a fatal disease characterized by destruction of the immune system and the inability to fight off life threatening opportunistic infections. Recent statistics (UNAIDS: Report on the Global HIV/AIDS Epidemic, December 1998), indicate that as many as 33 million people worldwide are infected with the virus. In addition to the large number of individuals already infected, the virus continues to spread. Estimates from 1998 point to close to 6 million new infections in that year alone. In the same year there were approximately 2.5 million deaths associated with HIV and AIDS.

There are currently a number of antiviral drugs available to combat the infection. These drugs can be divided into three classes based on the viral protein they target and their mode of action. In particular, saquinavir, indinavir, ritonavir, nelfmavir and amprenavir are competitive inhibitors of the aspartyl protease expressed by HIV. Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir are nucleoside reverse transcriptase inhibitors that behave as substrate mimics to halt viral cDNA synthesis. The non-nucleoside reverse transcriptase inhibitors, nevaripine, delavirdine and efavirenz inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism. Used alone these drugs are effective in reducing viral replication. The effect is only temporary as the virus readily develops resistance to all known agents. However, combination therapy has proven very effective at both reducing virus and suppressing the emergence of resistance in a number of patients. In the US, where combination therapy is widely available, the number of HIV-related deaths has declined (Palella, F. J.; Delany, K. M.; Moorman, A. C.; Loveless, M. O.; Furher, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J. Med. 1998, 338, 853-860).

Unfortunately, not all patients are responsive and a large number fail this therapy. In fact, approximately 30-50% of patients ultimately fail combination therapy. Treatment failure in most cases is caused by the emergence of viral resistance. Viral resistance in turn is caused by the rapid turnover of HIV-1 during the course of infection combined with a high viral mutation rate. Under these circumstances incomplete viral suppression caused by insufficient drug potency, poor compliance to the complicated drug regiment as well as intrinsic pharmacological barriers to exposure provides fertile ground for resistance to emerge. More disturbing are recent findings which suggest that low-level replication continues even when viral plasma levels have dropped below detectable levels (<50 copies/mL) (Carpenter, C. C.; Cooper, D. A.; Fischl, M. A.; Gatell, J. M.; Gazzard, B. G.; Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S.; Richman, D. D.; Saag, M. S.; Schechter, M.; Schooley, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.; Volberding, P. A. JAMA 2000, 283, 381-390). Clearly there is a need for new antiviral agents, preferably targeting other viral enzymes to reduce the rate of resistance and suppress viral replication even further.

HIV expresses three enzymes, reverse transcriptase, an aspartyl protease, and integrase. All three are targets for treating AIDS and HIV infection. HIV integrase catalyzes insertion of the viral cDNA into the host cell genome, which is a critical step in the viral life cycle. HIV integrase inhibitors belonging to a class of diketo acid compounds prevented viral integration and inhibited HIV-1 replication in cells (Hazuda et al. Science 2000, 287, 646). And recently, HIV integrase inhibitors have been accepted into clinical trials for treating AIDS and HIV infection (Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Pais and Burke Drugs Fut. 2002, 27, 1101).

DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their pharmaceutical compositions, and methods for inhibiting HIV integrase and treating those infected with HIV.

One aspect of the invention is a compound of Formula I

-   wherein: -   R¹ is (Ar¹)alkyl; -   R² is hydrogen, hydroxy, alkyl, or alkoxy; -   R³ is hydrogen, halo, hydroxy, cyano, alkyl, haloalkyl, alkoxy,     haloalkoxy, C₄₋₆lactamyl, N(R⁶)SO₂R⁷, N(R⁶)COR⁷, N(R⁶)CO₂R⁷, OCOR⁷,     OCO₂R⁷, OCON(R⁶)(R⁶), COR⁷, CO₂R⁶, CON(R⁶)(R⁶), SOR⁷, SO₂R⁷,     SO₂N(R⁶)(R⁶), P(O)(OR⁶)₂, or Ar²; -   R⁴ is hydrogen, halo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, or     haloalkoxy; -   R⁵ is hydrogen, halo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, or     haloalkoxy; -   R⁶is hydrogen, alkyl, or cycloalkyl; -   R⁷ is alkyl or cycloalkyl; -   R⁸ is hydrogen or alkyl; -   R⁹ is hydrogen, alkyl, cycloalkyl, hydroxyalkyl, (alkoxy)alkyl,     phenyl, or benzyl, wherein phenyl and benzyl are substituted with     0-2 substituents selected from the group consisting of halo, cyano,     alkyl, alkoxy, halolkyl, and haloalkoxy; -   Ar¹ is

-   Ar² is tetrazolyl, triazolyl, pyrazolyl, imidazolyl, pyrrolyl, or     dioxothiazinyl, and is substituted with 0-2 substituents selected     from the group consisting of amino, oxo, halo, and alkyl; and -   X—Y-Z is N(R⁹)C(R⁸)₂C(R⁸)₂, N(R⁹)C(R⁸)₂C(R⁸)₂C(R⁸)₂, or     N(R⁹)C(R⁸)₂C(R⁸)₂C(R⁸)₂C(R⁸)₂;     or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of Formula I where R¹ is

Another aspect of the invention is a compound of Formula I where R¹ is

provided that R³ is not hydrogen.

Another aspect of the invention is a compound of Formula I 1 where R¹ is

and R³ is C₄₋₆lactamyl, N(R⁶)SO₂R⁷, N(R⁶)COR⁷, N(R⁶)CO₂R⁷, OCOR⁷, OCO₂R⁷, OCON(R⁶)(R⁶), COR⁷, CO₂R⁶, CON(R⁶)(R⁶), SOR⁷, SO₂R⁷, SO₂N(R⁶)(R⁶), or Ar².

Another aspect of the invention is a compound of Formula I where R² is hydrogen.

Another aspect of the invention is a compound of Formula I where R³ is triazinyl substituted with 0-1 methyl groups; R⁴ is hydrogen, chloro, fluoro, or methyl; and R⁵ is hydrogen.

Another aspect of the invention is a compound of Formula I where R⁶ is hydrogen or alkyl.

Another aspect of the invention is a compound of Formula I where R⁷is alkyl.

Another aspect of the invention is a compound of Formula I where R⁸ is hydrogen or methyl.

Another aspect of the invention is a compound of Formula I where X—Y-Z is N(R⁹)CH₂CH₂, N(R⁹)CH₂CH₂CH₂, or N(R⁹)CH₂CH₂CH₂CH₂.

Another aspect of the invention is a compound according to one of the following structures:

Another aspect of the invention is a compound according to the following structure

Another aspect of the invention is a compound of Formula I where R⁹ is alkyl, cycloalkyl, hydroxyalkyl (alkoxy)alkyl, phenyl, or benzyl.

For a compound of Formula I, any scope of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Ar¹, Ar², and X—Y-Z can be used independently with any scope of any other variable.

“C₄₋₆lactamyl” means a lactam of 4 to 6 carbons, for example caprolactam.

“Dioxothiazinyl” means

Unless specified otherwise, these terms have the following meanings. “Alkyl” means a straight or branched alkyl group composed of 1 to 6 carbons. “Alkenyl” means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. “Alkynyl” means a straight or branched alkyl group composed of 2 to 6 carbons with at least one triple bond. “Cycloalkyl” means a monocyclic ring system composed of 3 to 7 carbons. “Haloalkyl” and “haloalkoxy” include all halogenated isomers from monohalo to perhalo. Terms with a hydrocarbon moiety (e.g. alkoxy) include straight and branched isomers for the hydrocarbon portion. “Aryl” includes carbocyclic and heterocyclic aromatic substituents. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention exist in stereoisomeric forms. The invention includes all stereoisomeric forms of the compounds including enantiomers and diastereromers. Methods of making and separating stereoisomers are known in the art.

The invention includes all tautomeric forms of the compounds. An example of a tautomeric pair is shown below.

Synthetic Methods

The compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section. The variables shown in the synthetic schemes are distinct from and should not be confused with the variables in the claims or the rest of the specification. The variables in the schemes are meant only to illustrate how to make some of the compounds of this invention.

Some formula I compounds can be synthesized from an appropriately substituted heterocycle I-1 according to Scheme I, where R_(a) and P can serve as protecting groups (see Greene, T. W. and Wutz, P. G. M. Protective Groups in Organic Synthesis, Second Edition, 1991, John Wiley and Sons, New York). When P is benzyl or substituted benzyl it can be removed by hydrogenolysis (H₂—Pd/C) or acid hydrolysis (trifluoroacetic acid) to yield intermediate I-2. I-2 can be transaminated to I-4 by reaction with amine I-3. When R_(a) is a lower alkyl group, R_(a) can be removed under ester hydrolysis conditions, such as treatment with NaOH, LiOH, or KOH to deliver the corresponding carboxylic acid I-5. Alternatively, R_(a) can be removed by nucleophilic displacement using NaI. When R_(a) is benzyl and substituted benzyl, R_(a) can be removed by hydrogenolysis. Intermediate I-5 can be coupled using amide bond forming reagents such as DCC, PyBOP, BOP or other reagents (see March, J. Advanced Organic Chemistry, Fourth Edition 1992 John Wiley & Sons, New York). The resulting intermediate I-6 can be deprotected as described for intermediate I-1.

Some bicyclic heterocycles can be synthesized according to a variety of methods, some examples of which are illustrated in Scheme II. Using methods similar to that described in Sunderland, J. S.; Botta, M.; Aime, S.; Raymond, K. N. Inorg. Chem. 2001, 40, 6756-6756, II-1 and II-2 can be condensed to provide intermediate II-3. Intermediate II-3 can be reacted with thiourea to yield pyrimidinone II-4. Pyrimidinone II-4 can be transformed to II-5 by addition of an appropriately substituted ethylamine to the N-3 of the pyrimidinone. The sulfide of II-4 can be activated for nucleophilic displacement by treating with an appropriate oxidizing agent such as mCPBA to form the sulfone II-6. The sulfone can be displaced by the appropriately functionalized amino group to yield II-7. This compound can be carried on to the final product according to the methods described in Scheme I.

In Scheme III, the intermediate II-3 is prepared in the same manner as in Scheme II. Condensation with a cyclic guanidine, such as III-2 provides the bicyclic intermediate III-3, which in turn is carried on to final compound as described in Scheme I.

Biological Methods

Another aspect of the invention is a method for inhibiting HIV integrase comprising contacting a compound of Formula I with HIV integrase.

Another aspect of the invention is a method for inhibiting HIV viral cDNA integration into human DNA comprising administering an effective amount of a compound of Formula I to a human cell infected with HIV.

HIV-Integrase Inhibition Activity. To evaluate in-vitro activity against HIV-integrase, 5 pmole of biotin labeled substrate DNA was bound to 100 μg of Streptavidin coated PVT SPA beads (Amersham Pharmacia Biotech). Recombinant integrase (0.26 ng) was incubated with the beads for 90 min at 37° C. Unbound enzyme was removed by washing the complex followed by addition of inhibitors and 0.1 fmol of P33 labeled target DNA. The reaction was stopped by adding EDTA to a final concentration of 10 mM. Samples were counted in TopCountNXT (Packard) and the CPM was used as a measure of integration. The reaction condition was as described in A. Engelman and R. Craigie, J. Virol. 69, 5908-5911 (1995). The sequences of substrate and target DNA were described in Nucleic Acid Research 22,1121-1122 (1994). Results shown in the Table 1. Activity equal to A refers to a compound having IC₅₀=0.005 to 0.010 μM while B and C denote compounds having IC₅₀=0.010 to 0.030 μM and IC₅₀>0.030 μM respectively.

TABLE 1 Example Activity 1 B 2 B 3 B 4 B 5 B 6 B 7 B 8 A 9 B 10 C 11 A 12 B 13 B 14 B 15 A 16 C 17 B 18 B 19 B 20 A 21 A 22 B 23 A 24 A 25 B 26 B 27 B 28 A 29 B 30 B 31 B 32 A 33 A 34 A 35 B 36 B 37 B 38 C 39 C 40 A 41 B 42

Inhibition of HIV replication. A recombinant NL-Rluc virus was constructed in which a section of the nef gene from NL4-3 was replaced with the Renilla Luciferase gene. The NL-RLuc virus was prepared by co-transfection of two plasmids, pNLRLuc and pVSVenv. The pNLRLuc contains the NL-Rluc DNA cloned into pUC18 at the PvuII site, while the pVSVenv contains the gene for VSV G protein linked to an LTR promoter. Transfections were performed at a 1:3 ratio of pNLRLuc to pVSVenv on 293T cells using the LipofectAMINE PLUS kit from Invitrogen (Carlsbad, Calif.) according to manufactures instruction, and the pseudotype virus generated was titered in MT-2 cells.

Susceptibility of viruses to compounds was determined by incubation in the presence of serial dilutions of the compound. The 50% effective concentration (EC₅₀) was calculated by using the exponential form of the median effect equation where (Fa)=1/[1+(ED₅₀/drug conc.)^(m)] (Johnson V A, Byington R T. Infectivity Assay. In Techniques in HIV Research. ed. Aldovini A, Walker B D. 71-76. New York: Stockton Press. 1990). The anti-viral activity of compounds was evaluated under three serum conditions, 10% FBS, 15 mg/ml human serum albumin/10% FBS or 40% human serum/5% FBS, and the results from at least 2 experiments were used to calculate the EC₅₀ values. Results are shown in the Table 2. Activity equal to A refers to a compound having EC₅₀=0.004 to 0.030 μM while B and C denote compounds with EC₅₀=0.030 to 0.1 μM and EC₅₀>0.1 μM respectively.

TABLE 2 Example Activity 1 C 2 C 3 C 4 C 5 C 6 C 7 C 8 C 9 A 10 A 11 C 12 C 13 C 14 A 15 A 16 B 17 B 18 B 19 B 20 B 21 A 22 A 23 A 24 A 25 A 26 A 27 A 28 A 29 C 30 C 31 C 32 C 33 C 34 A 35 B 36 C 37 C 38 C

Pharmaceutical Composition and Methods of Use

The compounds of this invention inhibit HIV integrase. HIV integrase inhibitors belonging to a class of diketo acid compounds prevented viral integration and inhibited HIV-1 replication in cells (Hazuda et al. Science 2000, 287, 646). Recently, HIV integrase inhibitors have been accepted into clinical trials for treating AIDS and HIV infection (Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Pais and Burke Drugs Fut. 2002, 27, 1101).

Accordingly, another aspect of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with a therapeutically effective amount of at least one other agent used for treatment of AIDS or HIV infection. Some suitable agents are nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.

Another aspect of the invention is a composition for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

“Combination,” “coadministration,” “concurrent,” and similar terms referring to the administration of a compound of Formula I with at least one anti-HIV agent mean that the components are part of a combination antiretroviral therapy or highly active antiretroviral therapy (HAART) as understood by practitioners in the field of AIDS and HIV infection.

“Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of AIDS and HIV infection. In general, the goals of treatment are suppression of viral load, restoration and preservation of immunologic function, improved quality of life, and reduction of HIV-related morbidity and mortality.

“Patient” means a person infected with the HIV virus and suitable for therapy as understood by practitioners in the field of AIDS and HIV infection.

“Treatment,” “therapy,” “regimen,” “HIV infection,” “ARC,” “AIDS” and related terms are used as understood by practitioners in the field of AIDS and HIV infection.

The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. A therapeutically effective amount is that which is needed to provide a meaningful patient benefit. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions.

Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred.

Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg.

Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other antiretroviral agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical judgment.

The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating AIDS and HIV infection. Some of these agents include HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integrase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, budding and maturation inhibitors, immunomodulators, and anti-infectives. In these combination methods, the compound of Formula I will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regime, however, will be determined by a physician using sound medical judgment.

Table 3 lists some agents useful in treating AIDS and HIV infection which are suitable for this invention.

TABLE 3 DRUG NAME MANUFACTURER INDICATION ANTIVIRALS 097 Hoechst/Bayer HIV infection, AIDS, (non-nucleoside reverse ARC transcriptase inhibitor) Amprenavir Glaxo Wellcome HIV infection, AIDS, 141 W94 ARC GW 141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIV infection, AIDS, GW 1592 ARC (RT inhibitor) Acemannan Carrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV infection, ARC, AL-721 Ethigen PGL HIV positive, AIDS (Los Angeles, CA) Alpha Interferon Glaxo Wellcome Kaposi's sarcoma HIV in combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC Neutralizes pH Concepts Labile alpha aberrant (Rockville, MD) Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases BMS-232623 Bristol-Myers Squibb/ HIV infection, AIDS, (CGP-73547) Novartis ARC (protease inhibitor) BMS-234475 Bristol-Myers Squibb/ HIV infection, AIDS, (CGP-61755) Novartis ARC (protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis Immune globin Cytovene Syntex Sight threatening Ganciclovir CMV peripheral, CMV retinitis Delaviridine Pharmacia-Upjohn HIV infection, AIDS, (RT inhibitor) ARC Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive asymptomatic Japan) ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddI Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC; combination with AZT/d4T DMP-450 AVID HIV infection, AIDS, (protease inhibitor) (Camden, NJ) ARC Efavirenz DuPont Merck HIV infection, AIDS, (DMP 266) ARC (−)6-Chloro-4-(S)- cyclopropylethynyl- 4(S)-trifluoro- methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE (non-nucleoside RT inhibitor) EL10 Elan Corp, PLC HIV infection (Gainesville, GA) Famciclovir Smith Kline herpes zoster, herpes simplex FTC Emory University HIV infection, AIDS, (reverse transcriptase ARC inhibitor) GS 840 Gilead HIV infection, AIDS, (reverse transcriptase ARC inhibitor) HBY097 Hoechst Marion HIV infection, AIDS, (non-nucleoside reverse Roussel ARC transcriptaseinhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS, Kaposi's sarcoma, Interferon Beta (Almeda, CA) ARC Interferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-associated diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, (reverse transcriptase ARC, also with AZT inhibitor) Lobucavir Bristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection, AIDS, (protease inhibitor) Pharmaceuticals ARC Nevirapine Boeheringer HIV infection, AIDS, (RT inhibitor) Ingleheim ARC Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIV Phosphonoformate Products, Inc. infection, other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS, (protease inhibitor) ARC Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIV infection, AIDS, Tech (Houston, TX) ARC Ritonavir Abbott HIV infection, AIDS, (protease inhibitor) ARC Saquinavir Hoffmann- HIV infection, AIDS, (protease inhibitor) LaRoche ARC Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy- ARC thymidine Valaciclovir Glaxo Wellcome Genital HSV & CMV infections Virazole Viratek/ICN asymptomatic HIV- Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIV infection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies Tenofovir disoproxil, Gilead HIV infection, AIDS fumarate salt (Viread ®) (reverse transcriptase inhibitor) Combivir ® GSK HIV infection, AIDS (reverse transcriptase inhibitor) abacavir succinate GSK HIV infection, AIDS (or Ziagen ®) (reverse transcriptase inhibitor) Reyataz ® Bristol-Myers Squibb HIV infection, AIDS (atazanavir) Fuzeon Roche/Trimeris HIV infection, AIDS, (Enfuvirtide, T-20) viral fusion inhibitor Trizivir ® HIV infection, AIDS Kaletra ® Abbott HIV infection, AIDS ARC IMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn Advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX) CL246,738 American Cyanamid AIDS, Kaposi's sarcoma Lederle Labs EL10 Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor) Granulocyte Genetics Institute AIDS Macrophage Colony Sandoz Stimulating Factor Granulocyte Hoechst-Roussel AIDS Macrophage Colony Immunex Stimulating Factor Granulocyte Schering-Plough AIDS, combination Macrophage Colony w/AZT Stimulating Factor HIV Core Particle Rorer Seropositive HIV Immunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase in CD4 Interleukin-2 cell counts (aldeslukin) Immune Globulin Cutter Biological Pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's sarcoma, (New Orleans, LA) ARC, PGL IMREG-2 Imreg AIDS, Kaposi's sarcoma, (New Orleans, LA) ARC, PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma AIDS, Muramyl-Tripeptide Amgen in combination w/AZT Granulocyte Colony Stimulating Factor Remune Immune Response Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma, AIDS, Alfa 2a in combination w/AZT ARC SK&F106528 Smith Kline HIV infection Soluble T4 Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNF w/gamma Interferon ANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille Squibb Corp. Prevention of oral Nystatin Pastille candidiasis Ornidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL) Trimethoprim Antibacterial Trimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis Isethionate for Inhalation Spiramycin Rhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen-Pharm. Histoplasmosis; R51211 cryptococcal meningitis Trimetrexate Warner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemia assoc. Erythropoietin with AZT therapy Recombinant Human Growth Serono AIDS-related wasting, Hormone cachexia Megestrol Acetate Bristol-Myers Squibb Treatment of anorexia assoc. W/AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Norwich Eaton Diarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS

DESCRIPTION OF SPECIFIC EMBODIMENTS

Ethyl 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate

Diethyl oxalate (7.66 g, 52.4 mmol) and ethyl benzyloxyacetate (10.2 g, 52.5 mmol) in dry tetrahydrofuran (70 ml) were treated at 22° C. with sodium hydride (2.31 g of a 60% dispersion in mineral oil, 57.7 mmol). Ethanol (40 μl) was then added and the mixture was stirred under argon for 16 h. The tetrahydrofuran was then concentrated under reduced pressure and the residue was treated with a mixture of 1-methyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (9.45 g, 52.5 mmol) (J. V. Grennhill et al. J. Chem. Soc. Perkin Trans.II, 1985, 1255-1264) in a solution of sodium ethoxide (26.0 mmol, prepared from 0.60 g of sodium) in ethanol (70 ml) and the resulting mixture was heated at 60° C. for 3 h. Acetic acid (2 ml) was added and the ethanol was evaporated under reduced pressure. The residue was diluted with ethyl acetate washed successively with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel (elution gradient of ethanol 0-20% in ethyl acetate) gave 5.33 g (30% yield) of intermediate 1 as white crystals; mp 135-137° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.32 (3H, t, J=7.1 Hz, CH₃), 3.03 (3H, s, NCH₃), 3.71 (2H, t, J=9.1 Hz, CH₂), 4.15 (2H, t, J=9.1 Hz, CH₂), 4.33 (2H, q, J=7.1 Hz, OCH₂), 5.10 (2H, s, OCH₂), 7.3-7.51 (5H, m, aromatics). Anal. Calcd for C₁₇H₁₉N₃O₄: C, 61.99, H 5.81; N, 12.75. Found: C, 61.73; H, 5.78; N, 12.73.

6-(Benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic Acid

A solution of ethyl 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.971 g, 2.95 mmol) in a mixture tetrahydrofuran (20 ml) and ethanol (20 ml) was treated with 15 ml of 1 N sodium hydroxide and the mixture was stirred at 40° C. for 30 min. The solvent was then concentrated under reduced pressure and the residue was acidified with 1 N hydrochloric acid (20 ml). The precipitate formed was filtered, washed with water and dried in vacuo to give 0.874 g (98% yield) of the title acid as a white solid; mp 203° C. (dec; ethyl acetate). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.87 (3H, s, NCH₃), 3.66 (2H, t, J=9 Hz, CH₂), 4.01 (2H, t, J=9 Hz, CH₂), 4.91 (2H, s, OCH₂), 7.3-7.45 (5H, m, aromatics). HRMS (ESI⁺) calculated for C₁₅H₁₆N₃O₄ [M+H⁺]: 302.1141. found: 302.1127.

N-(4-Fluorobenzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

A mixture of 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.393 g, 1.30 mmol) and 4-fluorobenzylamine (0.163 g, 1.30 mmol) in acetonitrile (15 ml) was treated at 25° C. with triethylamine (0.42 ml, 2.5 mmol) followed by benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.662 g, 1.49 mmol). After 3 h, the reaction mixture was diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residual solid from ethyl acetate gave 0.407 g (76% yield) of the title amide as white cubes; mp 189-191° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.02 (3H, s, NCH₃), 3.70 (2H, t, J=9 Hz, CH₂), 4.15 (2H, t, J=9 Hz, CH₂), 4.50 (2H, d, J=5.6 Hz, NCH₂), 5.11 (2H, s, OCH₂), 7.0 (2H, m, aromatics), 7.24 (2H, m, aromatics), 7.3-7.45 (SH, m, aromatics), 7.71 (1H, broad t, NH). Anal. Calcd for C₂₂H₂₁FN₄O₃: C, 64.69; H, 5.18; N, 13.71. Found: C, 64.41; H, 5.10; N, 13.72.

EXAMPLE 1

N-(4Fluorobenzyl)-6-hydroxy-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

A solution of N-(4-fluorobenzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.202 g, 0.495 mmol) in a mixture of ethyl acetate (150 ml) and ethanol (20 ml) at 25° C. was hydrogenated over 10% palladium on activated carbon (50 mg) and under one atmosphere of hydrogen for one hour to give 0.130 g (83% yield) of the title compound as white needles; mp 212° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.93 (3H, s, CH₃), 3.63 (2H, t, J=8.6 Hz, CH₂), 4.14 (2H, t, J=8.6 Hz, CH₂), 4.59 (2H, d, J=6.0 Hz, NCH₂), 7.07 (2H, m, aromatics), 7.33 (2H, m, aromatics), 7.89 (1H, broad t, NH), 11.57 (1H, s, OH). HRMS (ESI⁺) calculated for C₁₅H₁₆FN₄O₃ [M+H⁺]: 319.1206. found: 319.1191.

N-(4-Fluoro-3-methylbenzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Coupling of 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydromidazo[1,2-a]pyrimidine-7-carboxylic acid (0.439 g, 1.46 mmol) and 4-fluoro-3-methylbenzylamine (0.203 g, 1.46 mmol) as described for the synthesis of intermediate 3 gave 0.372 g (60% yield) of the title amide as white crystals; mp 182-184° C. (ethyl acetate). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.12 (3H, s, CH₃), 2.90 (3H, s, NCH₃), 3.66 (2H, t, J=8.6 Hz, CH₂), 4.02 (2H, t, J=8.6 Hz, CH₂), 4.33 (2H, d, J=6.0 Hz, NCH₂), 4.88 (2H, s, OCH₂), 6.97 (1H, m, aromatic), 7.11-7.2 (2H, m, aromatics), 7.3-7.4 (5H, m, aromatics), 8.81 (1H, broad t, NH). HRMS (ESI⁺) calculated for C₂₃H₂₄FN₄O₃ [M+H⁺]: 423.1832. found: 423.1827.

EXAMPLE 2

N-(4-Fluoro-3-methylbenzyl)-6-hydroxy-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Hydrogenolysis of N-(4-fluoro-3-methylbenzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.338 g, 0.80 mmol) as described for example 1 gave 0.191 g (72% yield) of the title compound as white crystals; mp 187-189° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.30 (3H, s, CH₃), 2.93 (3H, s, CH₃), 3.63 (2H, t, J=8.6 Hz, CH₂), 4.14 (2H, t, J=8.6 Hz, CH₂), 4.54 (2H, d, J=6.2 Hz, NCH₂), 7.0 (1H, m, aromatic), 7.12-7.18 (2H, m, aromatics), 7.87 (1H, broad t, NH), 11.59 (1H, s, OH). Anal. Calcd for C₁₆H₁₇FN₄O₃: C, 57.82; H, 5.15; N, 16.85. Found: C, 57.51; H, 5.27; N, 16.69.

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Coupling of 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 1.0 mmol) and 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.295 g, 1.0 mmol) as described for the synthesis of intermediate 3 gave 0.253 g (54% yield) of the title amide as white crystals; mp 184° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.78 (3H, d, J=4.5 Hz, NCH₃), 2.91 (3H, s, NCH₃), 3.66 (2H, t, J=8.9 Hz, CH₂), 4.02 (2H, t, J=8.9 Hz, CH₂), 4.46 (2H, d, J=6.2 Hz, NCH₂), 4.90 (2H, s, OCH₂), 7.04 (1H, m, aromatic), 7.25 (1H, dd, J=2.6 Hz and J=9.1 Hz, aromatic), 7.29-7.46 (6H, m, aromatics), 8.49 (1H, broad q, NH), 8.78 (l H, broad t, NH). HRMS (ESI⁺) calculated for C₂₄H₂₅FN₅O₄ [M+H⁺]: 466.1891. found: 466.1899.

EXAMPLE 3

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-hydroxy-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Hydrogenolysis of N-(4-fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.223 g, 0.48 mmol) as described for example 1 gave 0.048 g (27% yield) of the title compound a white solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.80 (3H, d, J=4.5 Hz, CH₃), 2.89 (3H, s, NCH₃), 3.56 (2H, t, J=8.6 Hz, CH₂), 3.97 (2H, t, J=8.6 Hz, CH₂), 4.53 (2H, d, J=6.5 Hz, NCH₂), 7.27-7.4 (3H, m, aromatics), 8.54 (1H, broad q, NH), 9.18 (1H, broad t, NH), 11.60 (1H, s, OH). HRMS (ESI⁺) calculated for C₁₇H₁₉FN₅O₄ [M+H⁺]: 376.1421. found: 376.1410.

1-Isopropyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide

A solution of N-isopropylethylenediamine (10.0 g, 0.097 mol) in methanol (10 ml) was cooled to 0° C. and treated dropwise with a solution of cyanogen bromide (10.37 g, 0.098 mol) in methanol (25 ml) while maintaining the temperature below 10° C. The reaction mixture was then heated to 80° C. for 45 min, cooled and concentrated under reduced pressure. Crystallization of the residue from cold ethanol gave 10.4 g (50% yield) of the title product as white crystals; mp 154-155° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.27 (6H, d, J=6.6 Hz, 2×CH₃), 3.57-3.75 (4H, m, 2×CH₂), 4.41 (1H, m, CH).

Ethyl 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate

Reaction of the adduct of diethyl oxalate (7.26 g, 49.7 mmol), ethyl benzyloxyacetate (9.65 g, 49.7 mmol) and sodium hydride (2.19 g of a 60% dispersion in mineral oil, 54.7 mmol) with 1-isopropyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (10.33 g, 49.7 mmol) as described for intermediate 1 gave 6.79 g (38% yield) of the title ester as white crystals; mp 131-132° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.22 (6H, d, J=6.8 Hz, 2×CH₃), 1.31 (3H, t, J=7.1 Hz, CH₃), 3.66 (2H, t, J=9 Hz, CH₂), 4.13 (2H, t, J=9 Hz, CH₂), 4.31 (2H, q, J=7.1 Hz, OCH₂), 4.40 (1H, m, CH), 5.08 (2H, s, OCH₂), 7.3-7.39 (3H, m, aromatics), 7.49 (2H, m, aromatics). Anal. Calcd for C₁₉H₂₃N₃O₄: C, 63.85; H, 6.48, N 11.75. Found: C, 63.57; H, 6.76; N, 11.98.

6-(Benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid

Saponification of ethyl 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (2.00 g, 5.60 mmol) as described for intermediate 2 gave 1.84 g (100% yield) of the title acid as a white solid; mp 163-165° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.23 (6H, d, J=6.7 Hz, 2×CH₃), 3.67 (2H, t, J=9 Hz, CH₂), 4.14 (2H, t, J=9 Hz, CH₂), 4.34 (1H, m, CH), 5.23 (2H, s, OCH₂), 7.3-7.39 (3H, m, aromatics), 7.57 (2H, m, aromatics). HRMS (ESI⁺) calculated for C₁₇H₂₀N₃O₄ [M+H⁺]: 330.1454. found: 330.1458.

N-(4-Fluorobenzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 4-fluorobenzylamine (0.120 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.385 g (96% yield) of the title amide as white crystals; mp 166-167° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.23 (6H, d, J=6.8 Hz, 2×CH₃), 3.67 (2H, t, J=9 Hz, CH₂), 4.14 (2H, t, J=9 Hz, CH₂), 4.42 (1H, m, CH), 4.50 (2H, d, J=6.0 Hz, NCH₂), 5.09 (2H, s, OCH₂), 7.0 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.3-7.37 (3H, m, aromatics), 7.46 (2H, m, aromatics), 7.69 (1H, broad t, NH). Anal. Calcd for C₂₄H₂₅FN₄O₃: C, 66.04; H, 5.77, N 12.83. Found: C, 65.84; H, 5.85; N, 12.58.

EXAMPLE 4

N-(4-Fluorobenzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Hydrogenolysis of N-(4-fluorobenzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.200 g, 0.46 mmol) as described for example 1 gave 0.134 g (84% yield) of the title compound as a white solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.21 (6H, d, J=6.8 Hz, 2×CH₃), 3.60 (2H, t, J=8.6 Hz, CH₂), 4.13 (2H, t, J=8.6 Hz, CH₂), 4.22 (1H, m, CH), 4.59 (2H, d, J=6.3 Hz, NCH₂), 7.07 (2H, m, aromatics), 7.33 (2H, m, aromatics), 7.88 (1H, broad t, NH),11.51 (1H, broad, OH). HRMS (ESI⁺) calculated for C₁₇H₂₀FN₄O₃ [M+H⁺]: 347.1519. found: 347.1520.

N-(4-Fluoro-3-methylbenzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Coupling of 6-(benzyloxy) 1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 4-fluoro-3-methylbenzylamine (0.133 g, 0.95 mmol) as described for the synthesis of intermediate 3 gave 0.384 g (93% yield) of the title amide as white crystals (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.23 (6H, d, J=6.6 Hz, 2×CH₃), 2.25 (3H, broad d, J=1.8 Hz, CH₃), 3.67 (2H, t, J=9 Hz, CH₂), 4.13 (2H, t, J=9 Hz, CH₂), 4.41 (1H, m, CH), 4.46 (2H, d, J=5.8 Hz, NCH₂), 5.08 (2H, s, OCH₂), 6.94 (1H, m, aromatic), 7.04-7.08 (1H, m, aromatic), 7.11 (1H, m, aromatic), 7.3-7.36 (3H, m, aromatics), 7.42-7.46 (2H, m, aromatics), 7.69 (1H, broad t, NH). HRMS (ESI⁺) calculated for C₂₅H₂₈FN₄O₃ [M+H⁺]: 451.2145. found: 451.2141.

EXAMPLE 5

N-(4-Fluoro-3-methylbenzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Hydrogenolysis of N-(4-fluoro-3-methylbenzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.200 g, 0.44 mmol) as described for example 1 gave 0.130 g (81% yield) of the title compound a white solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.21 (6H, d, J=6.8 Hz, 2×CH₃), 2.29 (3H, d, J=1.7 Hz, CH₃), 3.60 (2H, t, J=8.5 Hz, CH₂), 4.13 (2H, t, J=8.5 Hz, CH₂), 4.22 (1H, m, CH), 4.55 (2H, d, J=6.4 Hz, NCH₂), 7.0 (1H, m, aromatic), 7.15 (2H, m, aromatics), 7.86 (1H, broad t, NH), 11.54 (1H, broad, OH). HRMS (ESI⁺) calculated for C₁₈H₂₂FN₄O₃ [M+H⁺]: 361.1676. found: 361.1691.

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.210 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.328 g (72% yield) of the title amide as white crystals; mp 197-198° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.23 (6H, d, J=6.8 Hz, 2×CH₃), 2.98 (3H, d, J=5 Hz, NCH₃), 3.66 (2H, t, J=9 Hz, CH₂), 4.12 (2H, t, J=9 Hz, CH₂), 4.43 (1H, m, CH), 4.48 (2H, d, J=6.3 Hz, NCH₂), 5.09 (2H, s, OCH₂), 7.05 (1H, m, aromatic), 7.13-7.17 (2H, m, aromatics), 7.3-7.35 (4H, m, NH and aromatics), 7.43-7.46 (2H, m, aromatics), 8.35 (1H, broad t, NH). Anal. Calcd for C₂₆H₂₈FN₅O₄: C, 63.27; H, 5.71; N, 14.19. Found: C, 63.06; H, 5.65; N, 14.02.

EXAMPLE 6

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Hydrogenolysis of N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.200 g, 0.40 mmol) as described for example 1 gave 0.125 g (77% yield) of the title compound white crystals; mp 205° C. (dec) (dichloromethane-ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.24 (6H, d, J=6.6 Hz, 2×CH₃), 3.04 (3H, d, J=5.0 Hz, NCH₃), 3.59 (2H, t, J=8.5 Hz, CH₂),4.09 (2H, t, J=8.5 Hz, CH₂),4.31 (1H, m, CH), 4.61 (2H, d, J=6.6 Hz, NCH₂), 6.42 (1H, broad, NH), 7.10-7.20 (2H, m, aromatics), 7.49 (1H, dd, J=5.5 Hz and J=8.5 Hz, aromatic), 8.65 (1H, broad t, NH), 11.45 (1H, broad, OH). Anal. Calcd for C₁₉H₂₂FN₅O₄: C, 56.57; H, 5.49; N, 17.36. Found: C 56.34; H, 5.24; N, 17.26.

N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and (4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride (0.210 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.349 g (76% yield) of the title amide as white crystals; mp 171-172° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.24 (6H, d, J=6.8 Hz, 2×CH₃), 3.66 (2H, t, J=9 Hz, CH₂), 4.13 (2H, t, J=9 Hz, CH₂), 4.41 (2H, d, J=6.3 Hz, NCH₂), 4.43 (1H, m, CH), 5.10 (2H, s, OCH₂), 7.06 (1H, dd, J=2.6 Hz and J=8.6 Hz, aromatic), 7.17 (1H, m, aromatic), 7.29-7.31 (3H, m, aromatics), 7.45-7.48 (2H, m, aromatics), 7.71 (1H, dd, J=5.9 Hz and J=8.6 Hz, aromatic), 8.0 (1H, s, CH), 8.36 (1H, broad t, NH), 8.39 (1H, s, CH). Anal. Calcd for C₂₆H₂₆FN₇O₃: C, 62.01; H, 5.20; N, 19.47. Found: C, 62.00; H, 5.20; N, 19.50.

EXAMPLE 7

N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Hydrogenolysis of N-(4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.200 g, 0.40 mmol) as described for example 1 gave 0.134 g (82% yield) of the title compound white crystals (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.27 (6H, d, J=6.5 Hz, 2×CH₃), 3.60 (2H, t, J=8.5 Hz, CH₂), 4.12 (2H, t, J=8.5 Hz, CH₂), 4.25 (1H, m, CH), 4.48 (2H, d, J=6.8 Hz, NCH₂), 7.13 (1H, dd, J=2.5 Hz and J=8.4 Hz, aromatic), 7.24 (1H, m, aromatic), 7.69 (1H, dd, J=5.8 Hz and J=8.6 Hz, aromatic), 8.18 (1H, s, CH), 8.46 (1H, s, CH), 8.66 (1H, broad t, NH), 11.41 (1H, broad, OH). HRMS (ESI⁺) calculated for C₁₉H₂₁FN₇O₃ [M+H⁺]: 414.1690. found: 414.1677.

N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-benzyloxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.150 g, 0.45 mmol) and 4-fluoro-2-(N,N-dimethylsulfamoyl)benzylamine hydrochloride (0.147 g, 0.55 mmol) as described for the synthesis of intermediate 3 gave 0.190 g (75% yield) of the title amide as white crystals; mp 161-163° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.23 (6H, d, J=6.9 Hz, 2×CH₃), 2.85 (6H, s, 2×NCH₃), 3.65 (2H, t, J=9 Hz, CH₂),4.12 (2H, t, J=9 Hz, CH₂),4.40 (1H, m, CH), 4.81 (2H, d, J=6.6 Hz, NCH₂), 5.13 (2H, s, OCH₂), 7.22 (1H, m, aromatic), 7.28-7.34 (3H, m, aromatics), 7.49-7.52 (2H, m, aromatics), 7.55 (1H, dd, J=2.6 Hz and J=8.6 Hz, aromatic), 7.71 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.26 (1H, broad t, NH). Anal. Calcd for C₂₆H₃₀FN₅O₅S: C, 57.44; H, 5.56; N, 12.88. Found: C, 57.40; H, 5.46; N, 12.85.

EXAMPLE 8

N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

A solution of N-(4-fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-benzyloxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.155 g, 0.28 mmol) in trifluoroacetic acid (10 ml) was stirred at 25° C. for 72 h. The solvent was then evaporated under reduced pressure and the residue was purified by preparative HPLC (column YMC Pack C-18, 5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroacetic acid) to give 0.105 g (81% yield) of the title amide as a white solid.

¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.23 (6H, d, J=6.6 Hz, 2×CH₃), 2.91 (6H, s, 2×NCH₃), 3.59 (2H, t, J=8.5 Hz, CH₂), 4.11 (2H, t, J=8.5 Hz, CH₂), 4.24 (1H, m, CH), 4.84 (2H, d, J=6.8 Hz, NCH₂), 7.30 (1H, m, aromatic), 7.56 (1H, dd, J=2.8 Hz and J=8.3 Hz, aromatic), 7.70 (1H, dd, J=5.3 Hz and J=8.6 Hz, aromatic), 8.52 (1H, broad t, NH), 11.4 (1H, broad, OH). MS (ESI⁺) m/e 454 [M+H⁺].

N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (ethyl acetate-hexane). (75% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.23 (6H, d, J=6.9 Hz, 2×CH₃), 2.46 (3H, s, CH₃), 3.66 (2H, t, J=8.9 Hz, CH₂), 4.13 (2H, t, J=8.9 Hz, CH₂), 4.43 (1H, m, CH), 4.44 (2H, d, J=6.3 Hz, NCH₂), 5.10 (2H, s, OCH₂), 7.05 (1H, dd, J=2.7 Hz and J=8.6 Hz, aromatic), 7.14 (1H, m, aromatic), 7.27-7.28 (3H, m, aromatics), 7.42-7.45 (2H, m, aromatics), 7.69 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.26 (1H, broad t, NH), 8.26 (1H, s, CH). MS (ESI⁺) m/e 518 [M+H⁺].

EXAMPLE 9

N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White solid (100% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.24 (6H, d, J=6.6 Hz, 2×CH₃), 2.55 (3H, s, CH₃), 3.60 (2H, t, J=8.5 Hz, CH₂), 4.12 (2H, t, J=8.5 Hz, CH₂), 4.31 (1H, m, CH), 4.49 (2H, d, J=6.6 Hz, NCH₂), 7.10 (1H, dd, J=2.5 Hz and J=8.3 Hz, aromatic), 7.20 (1H, m, aromatic), 7.70 (1H, dd, J=6.0 Hz and J=8.7 Hz, aromatic), 8.35 (1H, s, CH), 8.61 (1H, broad t, NH), 11.56 (1H, s, OH). MS (ESI⁺) m/e 428 [M+H⁺].

N-(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 158-159° C. (ethyl acetate). (71% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.24 (6H, d, J=6.5 Hz, 2×CH₃), 2.44 (3H, s, CH₃), 3.66 (2H, t, J=8.8 Hz, CH₂), 4.13 (2H, t, J=8.8 Hz, CH₂), 4.23 (2H, d, J=6.3 Hz, NCH₂), 4.44 (1H, m, CH), 5.11 (2H, s, OCH₂), 6.99 (1H, dd, J=2.5 Hz and J=8.3 Hz, aromatic), 7.18 (1H, m, aromatic), 7.29-7.34 (3H, m, aromatics), 7.48-7.50 (2H, m, aromatics), 7.66 (1H, dd, J=6.0 Hz and J=8.7 Hz, aromatic), 7.89 (1H, s, CH), 8.10 (1H, broad t, NH). MS (ESI⁺) m/e 518 [M+H⁺].

EXAMPLE 10

N-(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 212° C. (ethyl acetate). (61% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.27 (6H, d, J=6.8 Hz, 2×CH₃), 2.47 (3H, s, CH₃), 3.60 (2H, t, J=8.6 Hz, CH₂), 4.11 (2H, t, J=8.6 Hz, CH₂), 4.28 (1H, m, CH), 4.31 (2H, d, J=6.5 Hz, NCH₂), 7.03 (1H, dd, J=2.8 Hz and J=8.3 Hz, aromatic), 7.26 (1H, m, aromatic), 7.67 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic), 8.00 (1H, s, CH), 8.35 (1H, broad t, NH), 11.35 (1H, s, OH). MS (ESI⁺) m/e 428 [M+H⁺].

1-Butyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide

Reaction of N-butylethylenediamine (10.7 g, 0.092 mol) with cyanogen bromide (9.76 g, 0.092 mol) as described in the preparation of intermediate 6 gave 11.77 g (57% yield) of the title compound as white crystals (ether-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.96 (3H, t, J=7.2 Hz, CH₃), 1.41 (2H, m, CH₂), 1.60 (2H, m, CH₂), 3.52 (2H, t, J=7.3 Hz, CH₂), 3.64-3.74 (4H, m, 2×CH₂), 7.58 and 7.7 (broad s, NH). MS (ESI⁺) m/e 142 [M+H⁺].

Ethyl 6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate

Reaction of the adduct of diethyl oxalate (5.71 g, 39.1 mmol), ethyl benzyloxyacetate (7.59 g, 39.1 mmol) and sodium hydride (1.71 g of a 60% dispersion in mineral oil, 42.7 mmol) with 1-butyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (8.68 g, 39.1 mmol) as described for intermediate 1 gave 5.55 g (38% yield) of the title ester as a clear oil. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.98 (3H, t, J=7.5 Hz, CH₃), 1.31 (3H, t, J=7.1 Hz, CH₃), 1.39 (2H, m, CH₂), 1.56-1.63 (2H, m, CH₂), 3.41 (2H, t, J=7.4 Hz, CH₂), 3.69 (2H, t, J=8.9 Hz, CH₂), 4.12 (2H, t, J=8.9 Hz, CH₂), 4.32 (2H, q, J=7.1 Hz, OCH₂), 5.09 (2H, s, OCH₂), 7.3-7.4 (3H, m, aromatics), 7.49 (2H, m, aromatics). MS (ESI⁺) m/e 372 [M+H⁺].

6-(Benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic Acid

Saponification of ethyl 6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (5.50 g, 14.8 mmol) as described for intermediate 2 gave 5.08 g (100% yield) of the title acid as a white solid; mp 132-135° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.98 (3H, t, J=7.3 Hz, CH₃), 1.34-1.44 (2H, m, CH₂), 1.56-1.63 (2H, m, CH₂), 3.39 (2H, t, J=7.4 Hz, CH₂), 3.71 (2H, t, J=8.9 Hz, CH₂), 4.15 (2H, t, J=8.9 Hz, CH₂), 5.23 (2H, s, OCH₂), 7.3-7.4 (3H, m, aromatics), 7.58 (2H, m, aromatics). MS (ESI⁺) m/e 344 [M+H⁺].

N-(4-Fluorobenzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Coupling of 6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.87 mmol) and 4-fluorobenzylamine (0.120 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.349 g (88% yield) of the title amide as white crystals; mp 107-109° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.96 (3H, t, J=7.3 Hz, CH₃), 1.33-1.43 (2H, m, CH₂), 1.56-1.63 (2H, m, CH₂), 3.41 (2H, t, J=7.4 Hz, CH₂), 3.70 (2H, t, J=8.9 Hz, CH₂), 4.13 (2H, t, J=8.9 Hz, CH₂), 4.50 (2H, d, J=5.8 Hz, NCH₂), 5.10 (2H, s, OCH₂), 7.0 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.33-7.37 (3H, m, aromatics), 7.46-7.48 (2H, m, aromatics), 7.68 (1H, broad t, NH). MS (ESI⁺) m/e 451 [M+H⁺].

EXAMPLE 11

N-(4-Fluorobenzyl)-1-butyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

Hydrogenolysis of N-(4-fluorobenzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide (0.350 g, 0.77 mmol) as described for example 1 gave 0.278 g (99% yield) of the title compound as a white solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.95 (3H, t, J=7.3 Hz, CH₃), 1.33-1.42 (2H, m, CH₂),1.54-1.67 (2H, m, CH₂), 3.31 (2H, t, J=7.2 Hz, CH₂), 3.63 (2H, t, J=8.9 Hz, CH₂),4.14 (2H, t, J=8.9 Hz, CH₂), 4.59 (2H, d, J=6.3 Hz, NCH₂), 7.07 (2H, m, aromatics), 7.33 (2H, m, aromatics), 7.86 (1H, broad t, NH), 11.52 (1H, s, OH). MS (ESI⁺) m/e 361 [M+H⁺].

N-(4-Fluoro-3-methylbenzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White solid, (90% yield).

¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.96 (3H, t, J=7.3 Hz, CH₃), 1.35-1.43 (2H, m, CH₂), 1.56-1.63 (2H, m, CH₂), 2.25 (3H, d, J=1.8 Hz, CH₃), 3.41 (2H, t, J=7.5 Hz, CH₂), 3.70 (2H, t, J=8.9 Hz, CH₂), 4.15 (2H, t, J=8.9 Hz, CH₂), 4.46 (2H, d, J=5.8 Hz, NCH₂), 5.09 (2H, s, OCH₂), 6.94 (1H, m, aromatic), 7.04-7.07 (1H, m, aromatic), 7.10 (1H, d, J=7.2 Hz, aromatic), 7.30-7.36 (3H, m, aromatics), 7.44-7.47 (2H, m, aromatics), 7.67 (1H, broad t, NH). MS (ESI⁺) m/e 465 [M+H⁺].

EXAMPLE 12

N-(4-Fluoro-3-methylbenzyl)-1-butyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White solid (94% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.95 (3H, t, J=7.3 Hz, CH₃), 1.28-1.42 (2H, m, CH₂), 1.54-1.63 (2H, m, CH₂), 2.29 (3H, d, J=1.8 Hz, CH₃), 3.31 (2H, t, J=7.3 Hz, CH₂), 3.63 (2H, t, J=8.9 Hz, CH₂), 4.14 (2H, t, J=8.9 Hz, CH₂), 4.54 (2H, d, J=6.4 Hz, NCH₂), 7.0 (1H, m, aromatic), 7.11-7.17 (2H, m, aromatics), 7.84 (1H, broad t, NH), 11.55 (1H, s, OH). MS (ESI⁺) m/e 375 [M+H⁺].

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White solid, (87% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.97 (3H, t, J=7.3 Hz, CH₃), 1.37-1.44 (2H, m, CH₂), 1.56-1.63 (2H, m, CH₂), 2.98 (3H, d, J=4.8 Hz, CH₃), 3.42 (2H, t, J=7.4 Hz, CH₂), 3.68 (2H, t, J=8.7 Hz, CH₂), 4.12 (2H, t, J=8.7 Hz, CH₂), 4.48 (2H, d, J=6.3 Hz, NCH₂), 5.10 (2H, s, OCH₂), 7.02-7.09 (2H, m, aromatic and NH), 7.14 (1H, dd, J=2.8 Hz and J=8.9 Hz, aromatic), 7.30-7.37 (4H, m, aromatics), 7.44-7.49 (2H, m, aromatics), 8.42 (1H, broad t, NH). MS (ESI⁺) m/e 508 [M+H⁺].

EXAMPLE 13

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-1-butyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 175-177° C. (ethyl acetate). (92% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.99 (3H, t, J=7.3 Hz, CH₃), 1.40-1.45 (2H, m, CH₂), 1.58-1.64 (2H, m, CH₂), 3.03 (3H, d, J=5.0 Hz, CH₃), 3.38 (2H, t, J=7.4 Hz, CH₂), 3.61 (2H, t, J=8.5 Hz, CH₂), 4.10 (2H, t, J=8.5 Hz, CH₂), 4.59 (2H, d, J=6.5 Hz, NCH₂), 6.40 (1H, broad q, NH), 7.11-7.15 (1H, m, aromatic), 7.18 (1H, dd, J=2.7 Hz and J=8.8 Hz, aromatic), 7.48 (1H, dd, J=5.4 Hz and J=8.5 Hz, aromatic), 8.81 (1H, broad t, NH), 11.48 (1H, s, OH). MS (ESI⁺) m/e 418 [M+H⁺].

N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White solid, (95% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.96 (3H, t, J=7.3 Hz, CH₃), 1.34-1.44 (2H, m, CH₂), 1.55-1.66 (2H, m, CH₂), 2.85 (6H, s, 2×NCH₃), 3.41 (2H, t, J=7.4 Hz, CH₂), 3.68 (2H, t, J=8.7 Hz, CH₂), 4.12 (2H, t, J=8.7 Hz, CH₂), 4.80 (2H, d, J=6.6 Hz, NCH₂), 5.12 (2H, s, OCH₂), 7.2-7.25 (1H, m, aromatic), 7.27-7.34 (3H, m, aromatics), 7.50-7.52 (2H, m, aromatics), 7.55 (1H, dd, J=2.7 Hz and J=8.5 Hz, aromatic), 7.71 (1H, dd, J=5.3 Hz and J=8.6 Hz, aromatic), 8.30 (1H, broad t, NH). MS (ESI⁺) m/e 558 [M+H⁺].

EXAMPLE 14

N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-1-butyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White solid (91% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.98 (3H, t, J=7.3 Hz, CH₃), 1.30-1.44 (2H, m, CH₂), 1.56-1.63 (2H, m, CH₂), 2.91 (6H, s, 2×NCH₃), 3.34 (2H, t, J=7.2 Hz, CH₂), 3.62 (2H, t, J=8.4 Hz, CH₂), 4.12 (2H, t, J=8.4 Hz, CH₂), 4.83 (2H, d, J=6.8 Hz, NCH₂), 7.26-7.31 (1H, m, aromatic), 7.55 (1H, dd, J=2.6 Hz and J=8.4 Hz, aromatic), 7.69 (1H, dd, J=5.3 Hz and J=8.6 Hz, aromatic), 8.55 (1H, broad t, NH), 11.40 (1H, s, OH). MS (ESI⁺) m/e 468 [M+H⁺].

N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 172-173° C. (ethyl acetate-hexane). (64% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.94 (3H, t, J=7.3 Hz, CH₃), 1.33-1.42 (2H, m, CH₂), 1.55-1.63 (2H, m, CH₂), 2.47 (3H, s, CH₃), 3.42 (2H, t, J=7.4 Hz, CH₂), 3.69 (2H, t, J=8.8 Hz, CH₂), 4.14 (2H, t, J=8.8 Hz, CH₂), 4.42 (2H, d, J=6.3 Hz, NCH₂), 5.11 (2H, s, OCH₂), 7.05 (1H, dd, J=2.7 Hz and J=8.5 Hz, aromatic), 7.11-7.16 (1H, m, aromatic), 7.24-7.28 (3H, m, aromatics), 7.41-7.44 (2H, m, aromatics), 7.68 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic), 8.24 (1H, broad t, NH), 8.29 (1H, s, CH). MS (ESI⁺) m/e 532 [M+H⁺]. Anal. Calcd for C₂₈H₃₀FN₇O₃: C, 63.26; H, 5.68; N, 18.44. Found: C, 63.18; H, 5.79; N, 18.32.

EXAMPLE 15

N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-1-butyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 214° C. (ethyl acetate). (93% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 0.95 (3H, t, J=7.4 Hz, CH₃), 1.33-1.43 (2H, m, CH₂), 1.56-1.64 (2H, m, CH₂), 2.55 (3H, s, CH₃), 3.38 (2H, t, J=7.2 Hz, CH₂), 3.62 (2H, t, J=8.5 Hz, CH₂), 4.13 (2H, t, J=8.5 Hz, CH₂), 4.49 (2H, d, J=6.5 Hz, NCH₂), 7.09 (1H, dd, J=2.6 Hz and J=8.4 Hz, aromatic), 7.17-7.22 (1H, m, aromatic), 7.69 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.32 (1H, s, CH), 8.57 (1H, broad t, NH), 11.60 (1H, s, OH). MS (ESI⁺) m/e 442 [M+H⁺].

1-Benzyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide

Reaction of N-benzylethylenediamine (15.02 g, 0.10 mol) with cyanogen bromide (10.6 g, 0.10 mol) as described in the preparation of intermediate 6 gave 23.82 g (93% yield) of the title product as white crystals; mp 202-204° C. (ethanol). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 3.48-3.56 (4H, m, 2×CH₂), 4.57 (2H, m, NCH₂), 7.30-7.44 (5H, m, aromatics), 7.92 and 8.18 (broad s, NH). Anal. Calcd for ClOH₁₃N₃.HBr: C, 46.89, H 5.50; N, 16.40. Found: C, 47.03; H, 5.49; N, 16.24.

Ethyl 1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate

Reaction of the adduct of diethyl oxalate (7.66 g, 52.4 mmol), ethyl benzyloxyacetate (10.2 g, 52.5 mmol) and sodium hydride (2.31 g of a 60% dispersion in mineral oil, 57.9 mmol) with 1-benzyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (13.39 g, 52.5 mmol) as described for intermediate 1 gave 3.98 g (18% yield) of the title ester as white crystals; mp 93° C. (ethyl acetate-hexane).

¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.33 (3H, t, J=7.1 Hz, CH₃), 3.56 (2H, t, J=9.1 Hz, CH₂), 4.12 (2H, t, J=9.1 Hz, CH₂), 4.35 (2H, q, J=7.1 Hz, OCH₂), 4.60 (2H, s, NCH₂), 5.12 (2H, s, OCH₂), 7.3-7.52 (10H, m, aromatics). Anal. Calcd for C₂₃H₂₃N₃O₄: C, 68.13; H, 5.71; N, 10.36. Found: C, 67.98; H, 5.70; N, 10.40.

1-Benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid

Saponification of ethyl 1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (2.04 g, 5.04 mmol) as described for intermediate 2 gave 1.90 g (100% yield) of the title acid as white crystals; mp 191° C. (dec), (ethyl acetate). ¹HNMR 400 MHz (DMSO-d,) δ (ppm): 3.58 (2H, t, J=8.8 Hz, CH₂), 4.05 (2H, t, J=8.8 Hz, CH₂), 4.53 (2H, s, NCH₂), 4.93 (2H, s, OCH₂), 7.32-7.45 (10H, m, aromatics), 13.41 (1H, s, OH). Anal. Calcd for C₂₁H₁₉N₃O₄: C 66.83; H, 5.07; N, 11.13. Found: C, 66.73; H, 5.16; N, 10.97.

N-(4-Fluorobenzyl)-1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 125° C. (ethyl acetate-hexane). (88% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.58 (2H, t, J=8.7 Hz, CH₂), 4.13 (2H, t, J=8.7 Hz, CH₂), 4.51 (2H, d, J=6.1 Hz, NCH₂), 4.60 (2H, s, NCH₂), 5.13 (2H, s, OCH₂), 7.0 (2H, m, aromatics), 7.24-7.38 (10H, m, aromatics), 7.47-7.49 (2H, m, aromatics), 7.71 (1H, broad t, NH). HRMS (ESI⁺) calculated for C₂₈H₂₆FN₄O₃ [M+H⁺]: 485.1989. found: 485.1993.

EXAMPLE 16

N-(4-Fluorobenzyl)-1-benzyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 225° C. (ethyl acetate-hexane). (97% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.53 (2H, t, J=8.6 Hz, CH₂), 4.13 (2H, t, J=8.6 Hz, CH₂), 4.50 (2H, s, NCH₂),4.59 (2H, d, J=6.1 Hz, NCH₂), 7.06 (2H, m, aromatics), 7.25-7.4 (7H, m, aromatics), 7.87 (1H, broad t, NH), 11.60 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₁H₂₀FN₄O₃ [M+H⁺]: 395.1519. found: 395.1508.

N-(4-Fluoro-3-methylbenzyl)-1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals. (81% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.24 (3H, s, CH₃), 3.57 (2H, t, J=8.7 Hz, CH₂), 4.12 (2H, t, J=8.7 Hz, CH₂), 4.47 (2H, d, J=5.6 Hz, NCH₂), 4.58 (2H, s, NCH₂), 5.12 (2H, s, OCH₂), 6.93 (1H, m, aromatic), 7.05-7.12 (2H, m, aromatics), 7.28-7.40 (8H, m, aromatics), 7.47-7.49 (2H, m, aromatics), 7.69 (1H, broad t, NH). HRMS (ESI⁺) calculated for C₂₉H₂₈FN₄O₃ [M+H⁺]: 499.2145. found: 499.2132.

EXAMPLE 17

N-(4-Fluoro-3-methylbenzyl)-1-benzyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 204° C. (dec) (ethyl acetate). (78% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.29 (3H, s, CH₃), 3.53 (2H, t, J=8.5 Hz, CH₂), 4.13 (2H, t, J=8.5 Hz, CH₂), 4.50 (2H, s, NCH₂),4.54 (2H, d, J=6.0 Hz, NCH₂), 7.02 (1H, m, aromatics), 7.1-7.4 (7H, m, aromatics), 7.84 (1H, broad t, NH), 11.63 (1H, s, OH). Anal. Calcd for C₂₂H₂,FN₄O₃: C, 64.69; H, 5.18; N, 13.71. Found: C, 64.42; H, 5.26; N, 13.55.

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White solid (95% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.97 (3H, d, J=5.14 Hz, CH₃), 3.55 (2H, t, J=8.8 Hz, CH₂), 4.09 (2H, t, J=8.8 Hz, CH₂), 4.50 (2H, d, J=6.28 Hz, NCH₂), 4.60 (2H, s, NCH₂), 5.12 (2H, s, OCH₂), 7.03-7.08 (2H, m, aromatics), 7.14 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.28-7.48 (9H, m, NH and aromatics), 7.54-7.57 (2H, m, aromatics), 8.46 (1H, broad t, NH). HRMS (ESI⁺) calculated for C₃₀H₂₉FN₅O₄ [M+H⁺]: 542.2204. found: 542.2214.

EXAMPLE 18

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-1-benzyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 206° C. (dec) (ethyl acetate). (72% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.75 (3H, d, J=4.4 Hz, NCH₃), 3.49 (2H, t, J=8.3 Hz, CH₂), 3.99 (2H, t, J=8.3 Hz, CH₂), 4.54 (2H, d, J=6.0 Hz, NCH₂), 4.57 (2H, s, NCH₂), 7.25-7.4 (8H, m, aromatics), 8.53 (1H, broad, NH), 9.31 (1H, broad, NH), 11.64 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₃H₂₃FN₅O₄ [M+H⁺]: 452.1734. found: 452.1720.

N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White solid (91% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 3.57 (2H, t, J=8.7 Hz, CH₂), 4.04 (2H, t, J=8.7 Hz, CH₂), 4.30 (2H, d, J=6.05 Hz, NCH₂), 4.57 (2H, s, NCH₂), 4.91 (2H, s, OCH₂), 7.16 (1H, m, aromatic), 7.29-7.53 (12H, m, aromatics), 8.23 (1H, s, CH), 8.88 (1H, broad t, NH), 8.99 (1H, s, CH). HRMS (ESI⁺) calculated for C₃₀H₂₇FN₇O₃ [M+H⁺]: 552.2159. found: 552.2173.

EXAMPLE 19

N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-1-benzyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 242° C. (dec) (ethyl acetate). (74% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 3.49 (2H, t, J=8.4 Hz, CH₂), 4.00 (2H, t, J=8.4 Hz, CH₂), 4.41 (2H, d, J=6.2 Hz, NCH₂), 4.61 (2H, s, NCH₂), 7.3-7.56 (8H, m, aromatics), 8.24 (1H, s, CH), 9.03 (1H, s, CH), 9.28 (1H, broad t, NH), 11.49 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₃H₂₁FN₇O₃ [M+H⁺]: 462.1690. found: 462.1682.

1-Phenyl-4, 5-dihydro-1H-imidazol-2-amine hydrobromide

Reaction of N-phenylethylenediamine (9.80 g, 0.072 mol) with cyanogen bromide (7.62 g, 0.072 mol) as described in the preparation of intermediate 6 gave 11.76 g (67% yield) of the title product as white crystals from ethanol. ¹HNMR 400 MHz (DMSO-d,) δ (ppm): 3.68 (2H, t, J=8.7 Hz, CH₂), 4.08 (2H, t, J=8.7 Hz, CH₂), 7.40-7.54 (5H, m, aromatics), 8.08 (broad s, NH). MS (ESI⁺) m/e 162 [M+H⁺].

Ethyl 6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate

Reaction of the adduct of diethyl oxalate (7.06 g, 48.3 mmol), ethyl benzyloxyacetate (9.38 g, 48.3 mmol) and sodium hydride (2.12 g of a 60% dispersion in mineral oil, 53.1 mmol) with 1-phenyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (11.70 g, 48.3 mmol) as described for intermediate 1 gave 1.99 g (11% yield) of the title ester as white crystals; mp 132-134° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.33 (3H, t, J=7.1 Hz, CH₃), 4.23-4.29 (4H, m, 2×CH₂), 4.35 (2H, q, J=7.1 Hz, OCH₂), 5.18 (2H, s, OCH₂), 7.16 (1H, m, aromatic), 7.3-7.53 (7H, m, aromatics), 7.73 (2H, m, aromatics). Anal. Calcd for C₂₂H₂₁N₃O₄: C, 67.50; H, 5.40; N, 10.73. Found: C, 67.44; H, 5.68; N, 10.73.

6-(Benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic Acid

Saponification of ethyl 6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (1.94 g, 4.95 mmol) as described for intermediate 2 gave 1.78 g (98% yield) of the title acid as white crystals. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 4.17-4.20 (4H, m, 2×CH₂), 5.00 (2H, s, OCH₂), 7.13 (1H, m, aromatic), 7.35-7.46 (7H, m, aromatics), 7.78 (2H, m, aromatics), 13.52 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₀H₁₈N₃O₄ [M+H⁺]: 364.1297. found: 364.1292.

N-(4-Fluorobenzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 199-200° C. (dichloromethane-ethyl acetate). (85% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 4.22-4.31 (4H, m, 2×CH₂), 4.51 (2H, d, J=6.1 Hz, NCH₂), 5.19 (2H, s, OCH₂), 7.02 (2H, m, aromatics), 7.14-7.5 (10H, m, aromatics), 7.62 (1H, broad t, NH), 7.67-7.71 (2H, m, aromatics). HRMS (ESI⁺) calculated for C₂₇H₂₄FN₄O₃ [M+H⁺]: 471.1832. found: 471.1833.

EXAMPLE 20

N-(4-Fluorobenzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (dichloromethane-hexane). (81% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 4.16 (2H, m, CH₂), 4.28 (2H, m, CH₂), 4.56 (2H, d, J=6.0 Hz, NCH₂), 7.05 (2H, m, aromatics), 7.15 (1H, m, aromatic), 7.30 (2H, m, aromatics), 7.37 (2H, m, aromatics), 7.50 (2H, m, aromatics), 7.72 (1H, broad t, NH),11.69 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₀H₁₈FN₄O₃ [M+H⁺]: 381.1363. found: 381.1378.

N-(4-Fluoro-3-methylbenzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 147° C. (ethyl acetate). (86% yield). ¹HNMR 400 MHz (DMSO-dr) δ (ppm): 2.12 (3H, s, CH₃), 4.12-4.25 (4H, m, 2×CH₂), 4.38 (2H, d, J=6.1 Hz, NCH₂), 4.97 (2H, s, OCH₂), 6.99 (1H, m, aromatic), 7.12-7.21 (3H, m, aromatics), 7.33-7.43 (7H, m, aromatics), 7.81 (2H, m, aromatics), 8.82 (1H, broad t, NH). HRMS (ESI⁺) calculated for C₂₈H₂₆FN₄O₃ [M+H⁺]: 485.1989. found: 485.1976.

EXAMPLE 21

N-(4-Fluoro-3-methylbenzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (ethyl acetate). (61% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.22 (3H, s, CH₃), 4.14 (4H, broad s, 2×CH₂), 4.50 (2H, d, J=5.6 Hz, NCH₂), 7.11 (2H, m, aromatics), 7.20 (2H, m, aromatics), 7.4 (2H, m, aromatics), 7.8 (2H, m, aromatics), 8.83 (1H, broad t, NH), 1 2.06 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₁H₂₀FN₄O₃ [M+H⁺]: 95.1519. found: 395.1521.

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 194-195° C. (ethyl acetate). (76% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.79 (3H, d, J=4.52 Hz, NCH₃), 4.14-4.25 (4H, m, 2×CH₂), 4.49 (2H, d, J=6.5 Hz, NCH₂), 5.0 (2H, s, OCH₂), 7.08 (1H, m, aromatic), 7.14 (1H, m, aromatic), 7.29 (1H, dd, J=2.7 Hz and J=9.3 Hz, aromatic), 7.33-7.45 (8H, m, aromatics), 7.82 (2H, m, aromatics), 8.52 (1H, broad q, NH), 8.80 (1H, broad t, NH). Anal. Calcd for C₂₉H₂₆FN₅O₄: C, 66.02; H, 4.96; N, 13.27. Found: C, 65.77; H, 5.19; N, 13.28.

EXAMPLE 22

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (ethyl acetate). (60% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.88 (3H, d, J=4.5 Hz, NCH₃), 4.12 (4H, broad s, 2×CH₂), 4.54 (2H, d, J=6.6 Hz, NCH₂), 7.11 (1H, m, aromatic), 7.3-7.5 (5H, m, aromatics), 7.86 (2H, m, aromatics), 8.68 (H, broad q, NH), 9.18 (1H, broad, NH), 12.0 (11H, s, OH). HRMS (ESI⁺) calculated for C₂₂H₂₁FN₅O₄ [M+H⁺]: 438.1578. found: 438.1576.

N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 187-190° C. (ethyl acetate). (74% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 4.13-4.25 (4H, m, 2×CH₂), 4.33 (2H, d, J=6.08 Hz, NCH₂), 5.0 (2H, s, OCH₂), 7.11-7.17 (2H, m, aromatics), 7.32-7.43 (7H, m, aromatics), 7.47-7.58 (2H, m, aromatics), 7.76-7.81 (2H, m, aromatics), 8.29 (1H, s, CH), 8.80 (1H, broad t, NH), 9.0 (1H, s, CH). HRMS (ESI⁺) calculated for C₂₉H₂₅FN₇O₃ [M+H⁺]: 538.2003 found: 538.1993.

EXAMPLE 23

N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (dichloromethane-ethanol). (53% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 4.13 (4H, s, 2×CH₂), 4.46 (2H, d, J=6.1 Hz, NCH₂), 711 (1H, m, aromatic), 7.34-7.45 (3H, m, aromatics), 7.61 (2H, m, aromatics), 7.77 (2H, m, aromatics), 8.29 (1H, s, CH), 8.81 (1H, broad t, NH), 9.09 (1H, s, CH), 11.89 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₂H₁₉FN₇O₃ [M+H⁺]: 448.1533. found: 448.1550.

N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 147-148° C. (ethyl acetate). (84% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.33 (3H, s, CH₃),4.20-4.32 (4H, m, 2×CH₂), 4.46 (2H, d, J=6.5 Hz, NCH₂), 5.21 (2H, s, OCH₂), 7.07 (1H ,dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.10-7.18 (2H, m, aromatics), 7.27-7.35 (5H, m, aromatics), 7.42-7.46 (2H, m, aromatics), 7.69-7.73 (3H, m, aromatics), 8.26 (1H, s, CH), 8.29 (1H, broad t, NH). MS (ESI⁺) m/e 552 [M+H⁺].

EXAMPLE 24

N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (ethyl acetate). (71% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.23 (3H, s, CH₃), 4.18 (2H, m, CH₂), 4.29 (2H, m, CH₂), 4.49 (2H, d, J=6.6 Hz, NCH₂), 7.09-7.15 (2H, m, aromatics), 7.18-7.23 (1H, m, aromatic), 7.28-7.32 (2H, m, aromatics), 7.6-7.7 (3H, m, aromatics), 8.33 (1H, s, CH), 8.62 (1H, broad t, NH), 11.91 (1H, s, OH). MS (ESI⁺) m/e 462 [M+H⁺].

N-(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 181° C. (ethyl acetate). (72% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.44 (3H, s, CH₃),4.23-4.32 (6H, m, 2×CH₂ and NCH₂), 5.22 (2H, s, OCH₂), 7.00 (1H , dd, J=2.7 Hz and J=8.5 Hz, aromatic), 7.16-7.22 (2H, m, aromatics), 7.28-7.33 (3H, m, aromatics), 7.39-7.43 (2H, m, aromatics), 7.49-7.51 (2H, m, aromatics), 7.69-7.73 (3H, m, aromatics), 7.81 (1H, s, CH), 8.05 (1H, broad t, NH). Anal. Calcd for C₃₀H₂₆FN₇O₃: C, 65.32; H, 4.75; N, 17.77. Found: C, 65.03; H, 4.56; N, 17.49.

EXAMPLE 25

N-(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (65% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.50 (3H, s, CH₃), 4.19 (2H, m, CH₂), 4.28 (4H, m, 2×CH₂), 7.04 (1H, dd, J=2.5 Hz and J=8.3 Hz, aromatic), 7.15-7.27 (2H, m, aromatics), 7.44 (2H, m, aromatics), 7.65-7.75 (2H, m, aromatics), 7.90 (1H, s, CH), 8.42 (1H, broad t, NH), 11.87 (1H, s, OH). MS (ESI⁺) m/e 462 [M+H⁺].

N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (acetonitrile). (75% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.80 (6H, s, 2×NCH₃), 4.16-4.26 (4H, m, 2×CH₂), 4.72 (2H, d, J=6.4 Hz, NCH₂), 5.03 (2H, s, OCH₂), 7.13-7.23 (2H, m, aromatics), 7.32-7.46 (7H, m, aromatics), 7.57-7.63 (2H, m, aromatics), 7.80-7.82 (2H, m, aromatics), 8.83 (1H, broad t, NH). HRMS (ESI⁺) calculated for C₂₉H₂₉FN₅O₅S [M+H⁺]: 578.1873. found: 578.1852.

EXAMPLE 26

N-(4-Fluoro-2-(N,N-dimethylsulfamoyl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (ethyl acetate). (90% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.85 (6H, s, 2×NCH₃), 4.13 (4H, s, 2×CH₂), 4.82 (2H, d, J=6.6 Hz, NCH₂), 7.11 (1H, m, aromatic), 7.42 (2H, m, aromatics), 7.55-7.65 (3H, m, aromatics), 7.78 (2H, m, aromatics), 8.77 (1H, broad t, NH), 11.76 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₂H₂₃FN₅O₅S [M+H⁺]: 488.1404. found: 488.1419.

N-(4-Fluoro-2-(2-oxopyrrolidin-1-yl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (ethyl acetate). (58% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.23 (2H, m, CH₂), 2.58 (2H, t, J=8.0 Hz, CH₂), 3.79 (2H, t, J=7.0 Hz, CH₂), 4.15-4.30 (4H, m, 2×CH₂), 4.46 (2H, d, J=6.0 Hz, NCH₂), 5.22 (2H, s, OCH₂), 6.91 (1H, dd, J=2.6 Hz and J=9.4 Hz, aromatic), 6.99 (1H, m, aromatic), 7.14 (1H, m, aromatic), 7.30-7.46 (5H, m, aromatics), 7.44 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.50-7.52 (2H, m, aromatics), 7.69-7.71 (2H, m, aromatics), 7.95 (1H, broad t, NH). MS (ESI⁺) m/e 554 [M+H⁺].

EXAMPLE 27

N-(4-Fluoro-2-(2-oxopyrrolidin-1-yl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (78% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.15 (2H, m, CH₂), 2.55 (2H, t, J=7.9 Hz, CH₂), 3.81 (2H, t, J=6.9 Hz, CH₂), 4.13 (4H, broad s, 2×CH₂), 4.41 (2H, d, J=6.4 Hz, NCH₂), 7.07 (1H, m, aromatic), 7.18 (1H, m, aromatic), 7.28 (1H, dd, J=2.5 Hz and J=10 Hz, aromatic), 7.36-7.40 (2H, m, aromatics), 7.45 (1H, dd, J=6.5 Hz and J=8.6 Hz, aromatic), 7.82-7.84 (2H, m, aromatics), 8.87 (1H, broad t, NH), 12.10 (1H, s, OH). MS (ESI⁺) m/e 464 [M+H⁺].

N-(4-Fluoro-2-(2-oxoazetidin-1-yl)benzyl)-6-(benzyloxy)-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (ethyl acetate). (22% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.10 (2H, t, J=4.4 Hz, CH₂), 3.73 (2H, t, J=4.4 Hz, CH₂), 4.19-4.31 (4H, m, 2×CH₂), 4.60 (2H, d, J=6.3 Hz, NCH₂), 5.21 (2H, s, OCH₂), 6.88 (1H, m, aromatic), 6.93 (1H, dd, J=2.4 Hz and J=9.7 Hz, aromatic), 7.16 (1H, m, aromatic), 7.29-7.31 (3H, m, aromatics), 7.39-7.43 (2H, m, aromatics), 7.47-7.48 (2H, m, aromatics), 7.54 (1H, dd, J=6.3 Hz and J=8.3 Hz, aromatic), 7.70-7.72 (2H, m, aromatics), 8.25 (1H, broad t, NH). MS (ESI⁺) m/e 540 [M+H⁺].

EXAMPLE 28

N-(4-Fluoro-2-(2-oxoazetidin-1-yl)benzyl)-6-hydroxy-5-oxo-1-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals (dichloromethane). (67% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 3.17 (2H, t, J=4.4 Hz, CH₂), 3.82 (2H, t, J=4.4 Hz, CH₂), 4.13 (4H, broad s, 2×CH₂),4.59 (2H, d, J=6.6 Hz, NCH₂), 7.07-7.11 (2H, m, aromatics), 7.23 (1H, dd, J=2.5 Hz and J=10.4 Hz, aromatic), 7.37-7.41 (2H, m, aromatics), 7.45 (1H, dd, J=6.6 Hz and J=8.6 Hz, aromatic), 7.82-7.84 (2H, m, aromatics), 9.04 (1H, broad t, NH), 12.03 (1H, s, OH). MS (ESI⁺) m/e 450 [M+H⁺].

1-(2-Methoxyethyl)-4,5-dihydro-1H-imidazol-2-amine hydrobromide

Reaction of N-(2-methoxyethyl)ethylenediamine (16.0 g, 0.135 mol) (R. C. F. Jones and J. R. Nichols, Tetrahedron Lett., 1990, 31, 1767-1770) with cyanogen bromide (14.34 g, 0.135 mol) as described in the preparation of intermediate 6 gave 26.86 g (88% yield) of the title product as large white prisms (ethanol); mp 143-145° C.

¹HNMR 400.¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 3.28 (3H, s, OCH₃), 3.48 (4H, s, 2×CH₂), 3.52 (2H, m, CH₂), 3.67 (2H, m, CH₂), 7.87 (broad s, NH). Anal. Calcd for C₆H₁₃N₃O. HBr: C, 32.15; H, 6.29; N, 18.75. Found: C, 32.23; H, 6.14; N, 18.85.

Ethyl 6-(benzyloxy)-1-(2-methoxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate

Reaction of the adduct of diethyl oxalate (16.95 g, 0.116 mol), ethyl benzyloxyacetate (22.53 g, 0.116 mol) and sodium hydride (5.10 g of a 60% dispersion in mineral oil, 0.127 mol) with 1-(2-methoxyethyl)-4,5-dihydro-1H-imidazol-2-amine hydrobromide (26.0 g, 0.116 mol) as described for intermediate 1 gave 5.37 g (12% yield) of the title ester as a clear oil. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.31 (3H, t, J=7.1 Hz, CH₃), 3.38 (3H, s, OCH₃), 3.61 (4H, s, 2×CH₂), 3.84 (2H, t, J=8.9 Hz, CH₂), 4.14 (2H, t, J=8.9 Hz, CH₂), 4.32 (2H, q, J=7.1 Hz, OCH₂), 5.09 (2H, s, OCH₂), 7.3-7.38 (3H, m, aromatics), 7.49 (2H, m, aromatics). MS (ESI⁺) m/e 374 [M+H⁺].

6-(Benzyloxy)-1-(2-methoxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid

White crystals; mp 125-126° C. (ethyl acetate). (97% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.38 (3H, s, OCH₃), 3.61 (4H, s, 2×CH₂), 3.86 (2H, t, J=9.0 Hz, CH₂), 4.16 (2H, t, J=9.0 Hz, CH₂), 5.26 (2H, s, OCH₂), 7.35-7.40 (3H, m, aromatics), 7.57 (2H, m, aromatics). Anal. Calcd for C₁₇H₁₉N₃O₅: C, 59.12; H, 5.54; N, 12.16. Found: C, 59.04; H, 5.55; N, 12.10.

N-(4-Fluorobenzyl)-6-(benzyloxy)-1-(2-methoxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 150° C. (ethyl acetate). (79% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.38 (3H, s, OCH₃), 3.61 (4H, s, 2×CH₂), 3.84 (2H, t, J=8.9 Hz, CH₂), 4.14 (2H, t, J=8.9 Hz, CH₂), 4.49 (2H, d, J=6.1 Hz, NCH₂), 5.10 (2H, s, OCH₂), 6.99 (2H, m, aromatics), 7.24 (2H, m, aromatics), 7.33-7.36 (3H, m, aromatics), 7.43-7.45 (2H, m, aromatics), 7.67 (1H, broad t, NH). Anal. Calcd for C₂₄H₂₅FN₄O₄: C, 63.70; H, 5.56; N, 12.38; Found: C, 64.00; H, 5.41; N, 12.10.

EXAMPLE 29

N-(4-Fluorobenzyl)-6-hydroxy-1-(2-methoxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 166° C. (ethanol). (96% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.38 (3H, s, OCH₃), 3.51 (2H, m, CH₂), 3.59 (2H, m, CH₂), 3.76 (2H, t, J=8.6 Hz, CH₂), 4.14 (2H, t, J=8.6 Hz, CH₂), 4.58 (2H, d, J=6.6 Hz, NCH₂), 7.07 (2H, m, aromatics), 7.32 (2H, m, aromatics), 7.85 (1H, broad t, NH), 11.57 (1H, s, OH). Anal. Calcd for C₁₇H₁₉FN₄O₄: C, 56.34; H, 5.28; N, 15.46. Found: C, 56.39; H, 5.37; N, 15.27.

1-(2-Hydroxyethyl)-4,5-dihydro-1H-imidazol-2-amine hydrobromide

Reaction of 2-(2-aminoethylamino)ethanol (8.0 g, 76.8 mmol) with cyanogen bromide (8.13 g, 76.8 mmol) as described in the preparation of intermediate 6 gave 13.27 g (82% yield) of the title product as large white prisms (ethanol); mp 112-115° C. ¹HNMR 400.¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 3.36 (2H, t, J=5.3 Hz, CH₂), 3.50-3.58 (4H, m, 2×CH₂), 3.69 (2H, m, CH₂), 4.97 (1H, t, J=5.0 Hz, OH), 7.73 and 7.85 (broad s, NH). Anal. Calcd for C₅H₁₁N₃0.HBr: C, 28.58; H, 5.75, N 20.00. Found: C, 28.79; H, 5.58; N, 20.12.

Ethyl 6-(benzyloxy)-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate

Reaction of the adduct of diethyl oxalate (14.61 g, 0.10 mol), ethyl benzyloxyacetate (19.42 g, 0.10 mol) and sodium hydride (4.40 g of a 60% dispersion in mineral oil, 0.11 mol) with 1-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-2-amine hydrobromide (21.0 g, 0.10 mol) as described for intermediate 1 gave 3.37 g (9% yield) of the title ester as white crystals; mp 104-106° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.32 (3H, t, J=7.1 Hz, CH₃), 3.53 (2H, m, CH₂), 3.83 (2H, t, J=8.9 Hz, CH₂), 3.90 (2H, m, CH₂), 4.19 (2H, t, J=8.9 Hz, CH₂), 4.32 (2H, q, J=7.1 Hz, OCH₂), 5.11 (2H, s, OCH₂), 7.35-7.40 (3H, m, aromatics), 7.51 (2H, m, aromatics). Anal. Calcd for C₁8H₂₁N₃O₅: C, 60.16; H, 5.89, N 11.69. Found: C, 60.24; H, 5.89; N, 11.77.

6-(Benzyloxy)-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid

White crystals (ethyl acetate). (80% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 3.36 (2H, t, J=5.8 Hz, CH₂), 3.58 (2H, broad t, CH₂), 3.76 (2H, t, J=9.1 Hz, CH₂), 4.02 (2H, t, J=9.1 Hz, CH₂), 4.85 (1H, broad, OH), 4.90 (2H, s, OCH₂), 7.34-7.43 (SH, m, aromatics), 13.3 (H, broad, OH). MS (ESI⁺) m/e 332 [M+H⁺].

Ethyl 6-hydroxy-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate

A solution of ethyl 6-(benzyloxy)-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (1.40 g, 3.89 mmol) in a mixture of ethyl acetate (300 ml) and ethanol (75 ml) at 25° C. was hydrogenated over 10% palladium on activated carbon (200 mg) and under one atmosphere of hydrogen for four hours to give 1.05 g (100% yield) of the title compound as light yellow needles; mp 155-156° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.44 (3H, t, J=7.1 Hz, CH₃), 3.46 (2H, m, CH₂), 3.75 (2H, t, J=8.3 Hz, CH₂), 3.92 (2H, m, CH₂), 4.20 (2H, t, J=8.3 Hz, CH₂), 4.43 (2H, q, J=7.1 Hz, OCH₂), 10.20 (1H, s, OH). Anal. Calcd for C₁₁H₁₅N₃O₅: C, 49.06; H, 5.61; N, 15.60. Found: C, 49.09, H, 5.73; N, 15.58.

EXAMPLE 30

N-(4-Fluorobenzyl)-6-hydroxy-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

A solution of ethyl 6-hydroxy-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.110 g, 0.408 mmol) and 4-fluorobenzylamine (0.200 g, 1.6 mmol) in anhydrous ethanol (5 ml) was heated under reflux for 6 h. The reaction mixture was then diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residual solid from ethanol gave 0.116 g (82% yield) of the title amide as white cubes; mp 203° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.54 (2H, t, J=5.0 Hz, CH₂), 3.80 (2H, t, J=8.5 Hz, CH₂), 3.89 (2H, t, J=5.0 Hz, CH₂), 4.15 (2H, t, J=8.5 Hz, CH₂), 4.57 (2H, d, J=6.0 Hz, NCH₂), 7.07 (2H, m, aromatics), 7.34 (2H, m, aromatics), 7.92 (1H, broad t, NH), 11.68 (1H, s, OH). Anal. Calcd for C₁₆H₁₇FN₄O₄: C, 55.17; H, 4.92; N, 16.08. Found: C, 55.22; H, 5.06; N, 15.89.

N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-(benzyloxy)-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White solid (67% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.55 (2H, t, J=5.0 Hz, CH₂), 3.81 (2H, t, J=8.7 Hz, CH₂), 3.88 (2H, t, J=5.0 Hz, CH₂), 4.17 (2H, t, J=8.7 Hz, CH₂), 4.42 (2H, d, J=6.1 Hz, NCH₂), 5.13 (2H, s, OCH₂), 7.06 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.18 (1H, m, aromatic), 7.25-7.31 (3H, m, aromatics), 7.39-7.41 (2H, m, aromatics), 7.69 (1H, dd, J=5.5 Hz and J=8.6 Hz, aromatic), 7.98 (1H, s, CH), 8.27 (1H, broad t, NH), 8.38 (1H, s, CH). MS (ESI⁺) m/e 506 [M+H⁺].

EXAMPLE 31

N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-6-hydroxy-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide

White crystals; mp 220-222° C. (ethanol). (86% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 3.42 (2H, t, J=5.8 Hz, CH₂), 3.62 (2H, m, CH₂), 3.68 (2H, t, J=8.5 Hz, CH₂), 3.98 (2H, t, J=8.5 Hz, CH₂), 4.41 (2H, d, J=6.0 Hz, NCH₂), 4.79 (1H, t, J=5.6 Hz, OH), 7.42 (1H, m, aromatic), 7.53 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.57 (1H, dd, J=2.7 Hz and J=9.3 Hz, aromatic), 8.34 (1H, s, CH), 9.06 (1H, s, CH), 9.16 (1H, broad t, NH), 11.43 (1H, s, OH). MS (ESI⁺) m/e 416 [M+H⁺].

Some other examples of formula I compounds are listed in table 4.

TABLE 4 Example Structure 32

33

34

35

36

37

38

39

40

41

42

43 

1. A compound of Formula I

wherein: R¹ is (Ar¹)alkyl; R² is hydrogen, hydroxy, alkyl, or alkoxy; R³ is hydrogen, halo, hydroxy, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, C₄₋₆lactamyl, N(R⁶)SO₂R⁷, N(R⁶)COR⁷, N(R⁶)CO₂R⁷, OCOR⁷, OCO₂R⁷, OCON(R⁶)(R⁶), COR⁷, CO₂R⁶, CON(R⁶)(R⁶), SOR⁷, SO₂R⁷, SO₂N(R⁶)(R⁶), P(O)(OR⁶)₂, or Ar²; R⁴ is hydrogen, halo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, or haloalkoxy; R⁵ is hydrogen, halo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, or haloalkoxy; R⁶ is hydrogen, alkyl, or cycloalkyl; R⁷ is alkyl or cycloalkyl; R⁸ is hydrogen or alkyl; R⁹ is hydrogen, alkyl, cycloalkyl, hydroxyalkyl, (alkoxy)alkyl, phenyl, or benzyl, wherein phenyl and benzyl are substituted with 0-2 substituents selected from the group consisting of halo, cyano, alkyl, alkoxy, halolkyl, and haloalkoxy; Ar¹ is

Ar² is tetrazolyl, triazolyl, pyrazolyl, imidazolyl, pyrrolyl, or dioxothiazinyl, and is substituted with 0-2 substituents selected from the group consisting of amino, oxo, halo, and alkyl; and X—Y-Z is N(R⁹)C(R⁸)₂C(R⁸)₂; or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1 where R¹ is


3. A compound of claim 1 where R¹ is

provided that R³ is not hydrogen.
 4. A compound of claim 1 where R¹ is

and R³ is C₄₋₆lactamyl, N(R⁶)SO₂R⁷, N(R⁶)COR⁷, N(R⁶)CO₂R⁷, OCOR⁷, OCO₂R⁷, OCON(R⁶)(R⁶), COR⁷, CO₂R⁶, CON(R⁶)(R⁶), SOR⁷, SO₂R⁷, SO₂N(R⁶)(R⁶), or Ar².
 5. A compound of claim 1 where R² is hydrogen.
 6. A compound of claim 1 where R³ is triazolyl substituted with 0-1 methyl groups; R⁴ is hydrogen, chloro, flouro, or methyl; and R⁵ is hydrogen.
 7. A compound of claim 1 where R⁶ is hydrogen or alkyl.
 8. A compound of claim 1 where R⁷ is alkyl.
 9. A compound of claim 1 where X—Y-Z is N(R⁹)CH₂CH₂.
 10. A compound of claim 1 where R⁹ is alkyl, cycloalkyl, hydroxyalkyl, (alkoxy)alkyl, phenyl, or benzyl.
 11. A compound selected from the group consisting of N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-methyl-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-methyl-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-methyl-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-(phenylmethyl)-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-(phenylmethyl)-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-(phenylmethyl)-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-(phenylmethyl)-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-hydroxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; 1-butyl-N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; 1-butyl-N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; 1-butyl-N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; 1-butyl-N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; 1-cyclohexyl-N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; 1-cyclohexyl-N-[(4-fluoro-3-methylphenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; 1-cyclohexyl-N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; 1-butyl-N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; 1-cyclohexyl-N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(2-oxo-1-azetidinyl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-hydroxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(2-oxo-1-pyrrolidinyl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[(4-fluorophenyl)methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(1-methylethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenyl-imidazo[1,2-a]pyrimidine-7-carboxamide; 1-butyl-N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-1,2,3,5-tetrahydro-6-hydroxy-1-(2-methoxyethyl)-5-oxo-imidazo[1,2-a]pyrimidine-7-carboxamide; and [5-fluoro-2-[[[(1,2,3,5-tetrahydro-6-hydroxy-5-oxo-1-phenylimidazo[1,2-a]pyrimidin-7-yl)carbonyl]amino]methyl]phenyl]-phosphonic acid, dimethyl ester; or a pharmaceutically acceptable salt thereof.
 12. A composition comprising a therapeutic amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
 13. A method for treating HIV infection comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
 14. The method of claim 13, further comprising a therapeutically effective amount of one or more other HIV treatment agents selected from the group consisting of HIV protease inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV-entry inhibitors, HIV integrase inhibitors, immunomodulators, or a combination thereof. 